Hepatocyte growth factor induces hepatocyte proliferation in vivo and allows for efficient retroviral-mediated gene transfer in mice
Hepatocyte growth factor induces hepatocyte proliferation in vivo and allows for efficient retroviral-mediated gene transfer in mice
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DOI：
10.1002/hep.510280317
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发表时间：
1998-09-01
期刊：
影响因子：
13.5
通讯作者：
Kay, MA
中科院分区：
文献类型：
--
作者：
Patijn, GA;Lieber, A;Kay, MA
重组逆转录病毒载体是一种诱人的将基因转移到肝脏的方法，因为它们整合到宿主细胞基因组中，并导致永久的基因表达。然而，有效的体内基因转移受到整合细胞分裂活跃的要求的限制，传统的诱导肝细胞增殖的方法存在通过毒素传递或外科肝部分切除来诱导肝细胞损伤的缺点。作为一种非创伤性的替代方案，我们证明了外源性肝细胞生长因子是一种强大而安全的成熟完整小鼠肝脏的有丝分裂原，当连续经门静脉注射人肝细胞生长因子(5 mg/kg/d)时，S天输注人肝细胞生长因子(5 mg/kg/d)可导致相对肝质量增加140%，并在4-5周内恢复正常，这清楚地表明外源生长因子可以在体内诱导强劲的肝脏增殖。此外，我们还发现肝细胞生长因子诱导的增殖不依赖于白介素6，白介素6是参与肝部分切除后肝再生的重要细胞因子。当重组逆转录病毒载体与HGF联合输注时，30%的肝细胞被稳定地转导，没有肝脏损伤或组织病理学的迹象，这些结果表明，在体内应用逆转录病毒载体可以获得临床相关的转导效率，而不会事先诱导肝脏损伤。所实现的肝脏基因转移水平具有治愈大量遗传性肝病的潜力。
Recombinant retroviral vectors are an attractive means of transferring genes into the liver because they integrate into the host cell genome and result in permanent gene expression. However, efficient in vivo gene transfer is limited by the requirement of active cell division for integration, Traditional approaches to induce liver proliferation have the disadvantage of inducing hepatocellular injury by delivery of toxins or by surgical partial hepatectomy. As a nontraumatic alternative, we show that exogenous hepatocyte growth factor (HGF) is a powerful and safe mitogen for the mature intact murine liver when delivered continuously into the portal vein, A S-day infusion of human HGF (5 mg/kg/d) resulted in > 140% increase in relative liver mass, which returned to normal in 4 to 5 weeks, This clearly shows that an exogenous growth factor can induce robust liver proliferation in vivo. In addition, we show that the HGF-induced proliferation was independent of interleukin-6, an essential cytokine involved in liver regeneration after partial hepatectomy. When recombinant retroviral vectors were infused in combination with HGF, 30% of hepatocytes were stably transduced with no indication of hepatic injury or histopathology, These results show the ability to obtain a clinically relevant transduction efficiency with retroviral vectors in vivo without the prior induction of liver injury. The level of hepatic gene transfer achieved has the potential to be curative for a large number of genetic liver diseases.